Greatwall promotes cell transformation by hyperactivating AKT in human malignancies

eLife

Jorge Vera¹  Gilles Gadea¹  Suzanne Vigneron¹  Anna Castro¹  Thierry Lorca¹  Veronique Gire¹  Isabelle Soubeyran²  Lydia Lartigue²  Frederic Chibon²  Maguy Del Rio³ 

[1] Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France;Department of Medical Oncology, Institut Bergonié, Institut National de la Santé et de la Recherche Medicale, Université Bordeaux Segalen, Bordeux, France;Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, Montpellier, France;

关键词: Greatwall;    Akt;    PHLPP;    oncogene;    PP2A;    cell invasion;   

DOI  :  10.7554/eLife.10115

来源: DOAJ

【 摘 要 】

The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL overexpression could participate in cancer development. We show that GWL overexpression promotes cell transformation and increases invasive capacities of cells through hyperphosphorylation of the oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and subsequent SCF-dependent degradation of the PHLPP phosphatase responsible for AKT dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in human colorectal tumoral tissues. Thus, GWL is a human oncoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies.

【 授权许可】

Unknown